Diabetic retinopathy (DR) is the leading cause of blindness in people aged 20-74 years in the United States. Although retinopathy is more common in type 1 diabetes, the majority of new cases are due to type 2 diabetes (T2DM). The socioeconomic cost of DR is expected to escalate with the increasing prevalence of T2DM due to the aging of the American society and the rapid growth of minority populations with predilection to T2DM and its microvascular complications. Severe DR occurs only, however, in approximately one-third of patients, i.e., a subgroup that appears to be genetically predisposed to the disease. This proposal will focus on studying genetics of DR in Hispanics because they have a strong propensity for development of T2DM and DR. This proposal is a joint effort among the UCLA School of Medicine, Cedars-Sinai Medical Center, and the University of Wisconsin Ocular Epidemiology Reading Center. The clinical center at UCLA will target 225 large Hispanic families with 3-4 diabetic sibs. We estimate that 1,000 diabetic sib-pairs will be studied. The families will be ascertained through a proband with DR. Diabetic sibs will undergo phenotyping which will include collection of demographic and clinical data and an eye examination that will include assessment of visual acuity, measurement of intraocular pressure, and obtaining standard 7-field fundus photographs. Fundus photographs will be read and graded at the Wisconsin Ocular Epidemiology Reading Center. Using the sequential genome-wide test, we will perform a 10 cM genome-wide search when each batch of genotyping (96 samples) is completed to identify candidate regions. Non-parametric sib-pair linkage analysis and variance components linkage analysis will be utilized to identify regions that may contain genes contributing to DR. For the eight best regions identified with evidence for linkage, eight new markers will be genotyped to narrow the candidate region. Successful completion of this project will result in the initial phase in locating novel gene(s) that confer susceptibility to DR. Characterization of the products of these genes will enhance our understanding of the pathogenesis of DR and lead to development of new preventive and therapeutic strategies. Moreover, availability of genetic markers for DR will allow early identification of patients at risk who should be targeted for intensive glycemic and blood pressure control.